Emesis is the complex process in some warm-blooded animals, including humans, in which the stomach is evacuated through the esophagus and mouth due to strong muscular contractions in the abdomen. Commonly known as vomiting or retching, emesis is associated with nausea, malaise and general discomfort. The mechanism by which emesis is induced is complex. A detailed discussion of the process is disclosed in, for example, Mehernoor F. Watcha et al., "Postoperative Nausea and Vomiting", Anesthesiology, Vol. 67, pp. 162-184 (1992).
The biochemical basis of emesis stems from the presence of an emesis center within the brain. This center is located specifically in a region designated anatomically as the area postrema. This specialized area of the brain is distinguished from other regions of the central nervous system by the fact that it does not have a blood brain barrier to prevent substances circulating in the blood from freely entering therein.
Current work suggests that neurons in the area postrema serve as sensors of noxious substances circulating in the blood. Once these substances enter the area postrema and are sensed by the neurons as harmful, a message in the form of electrical impulses is triggered to evacuate the gastrointestinal tract. The transmission of the electrical impulses is generated when sufficient positive charge has been built up in the neurons to cause depolarization and a subsequent action potential. This action potential causes the release of a chemical neurotransmitter molecule from the pre-synaptic terminal into the synaptic cleft. The neurotransmitter molecule diffuses from one neuron through extracellular fluid, across the synapse, to a membrane receptor molecule of a post-synaptic neuron. Several chemical neurotransmitter systems involved in emesis have been identified based on the type of neurotransmitter molecule and include those based on glutamate, dopamine and serotonin.
Efforts at mediating the emetic process have focused on disrupting these neurotransmitter systems. For example, inhibitors of dopamine and serotonin have been used to treat emesis as disclosed in Alison L. Jones et al., "Management of Vomiting Associated With Cytotoxic Therapy", Br. J. of Hosp. Med., Vol. 45, pp. 85-88 (February 1991). Glutamate receptor antagonists, such as kynurenic acid or 7-chlorokynurenate, have also been proposed as anti-emesis agents in John W. Olney, U.S. Pat. No. 5,039,528.
In the glutamate based neurotransmitter system, the presence of excess glutamate triggers an emesis response. Under these circumstances, excess calcium ions pass through a neuronal channel and upon entering the cell activate calmodulin. This substance activates nitric oxide synthase which in turn is responsible for converting L-arginine into citrulline and nitric oxide. Nitric oxide is believed to activate guanylate cyclase to produce cyclic GMP which may be directly involved in triggering the emetic process.
There are at least three distinct forms of nitric oxide synthase (NOS) found in the body. The first type is neuronal NOS found principally in the brain and in non-adrenergic, non-cholinergic (NANC) neurons in the gut. Endothelial NOS and inducible NOS (found in macrophages) are the second and third types. Endothelial NOS, found in the endothelial tissues, affects blood circulation by producing nitric oxide which acts as a vasodilator. Accordingly, endothelial NOS has been implicated in such conditions as hypertension, endotoxin shock (e.g. septic shock) and thrombosis.
Inducible NOS triggers the production of nitric oxide when the body is exposed to an endotoxin, and has been associated with such chronic ailments as ulcerative colitis and arthritis.
The production of nitric oxide can be inhibited by a class of compounds known as NOS inhibitors. For example, Interleukin-1 and lipopolysaccharides are known to inhibit the activity of macrophage NOS such as disclosed in Joseph R. Williamson et al., U.S. Pat. Nos. 5,245,970 and 5,246,971. Analogues of L-arginine including N.sup.G -monomethyI-L-arginine (L-NMMA), N-iminoethyI-L-ornithine (L-NIO) and N.sup.G -nitro-L-arginine methyl ester (L-NAME) have been shown to inhibit endothelial NOS. D. D. Rees et al., Br. J. Pharmacol, Vol. 101, pp. 746-752 (1990).
The present invention is premised on the discovery that compounds which effectively inhibit nitric oxide synthase, especially neuronal NOS, when administered in effective doses, can be employed as potent anti-emesis agents.